The use of estrogens in the course of treatment of a variety of conditions is well known. For example, the most prevalent form of oral contraception is the so-called combined oral contraceptive preparation, a pill that combines both estrogen and a progestin. Apparently, the progestin acts foremostly to block gonadotropin release while the estrogen component primarily provides endometrial control to diminish breakthrough bleeding. Another well-known use is long term estrogen replacement therapy which is common for post-menopausal and other estrogen deficient women. Other estrogen dependent conditions include endometriosis, uterine fibroid tumors (leiomyomata), pre-menstrual syndrome, dysfunctional uterine bleeding, breast tumors (benign and malignant) and the like.
Despite their value, estrogen treatments are also associated with undesirable side effects. For example, estrogen therapy has been associated with an increased incidence of endometrial cancer, especially due to the continual “unopposed” estrogen-induced proliferation of the endometrium. Other side effects include uterine bleeding and cyclotherapeutic withdrawal menstrual bleeding during a time in their lives when many women welcome cessation of menstrual bleeding as a normal occurrence in menopause. Estrogen therapy has also been implicated in the development of a variety of disorders including gallbladder disease, hypertension, abnormal glucose tolerance, hypercoagulable states and breast cancer, although some of these observations are antidotal in nature and have not been confirmed.
There have been numerous efforts to counteract the ill effects of estrogen therapy. For instance, attempts have been made to couple estrogen therapy with short periods of anti-estrogen supplementation. Another approach is to use anti-estrogens in place of the estrogen. Certain compounds are known as “anti-estrogens” because they can bind to the estrogen receptors and competitively block the binding of the more potent estrogens such as estradiol. Among the best known of these anti-estrogens are clomiphene and tamoxifen. However, all such anti-estrogens can be, in fact, active estrogens depending on the tissue, dose/regimen and hormonal milieu of the drug exposure. These are mixed function agonistic/antagonistic activities. The degree to which the anti-estrogen acts as an estrogen also depends on the particular material and the tissue site.
While anti-estrogen therapy has been successful, it is not without its own problems. As is know, there is a hypothalamic-pituitary-gonadal axis involved in endogenous hormone production. As estrogen binds to its receptors, there is a feedback mechanism which regulates the endogenous production of pituitary gonadotropins and, in turn, estrogen so that the hormonal milieu remains within the physiological range. When an anti-estrogen binds to the estrogen receptors, altered estrogen feedback mechanisms are implicated in a pharmacological manner compared to when estrogen binds normally. The anti-estrogens themselves can induce multiple follicular growth which, in turn, causes the production of endogenous ovarian estrogens. A favorable example is the use of clomiphene for ovulation induction. For the first anti-estrogen dose administration and continuing for some period of time, the endogenous estrogen produced as a consequence of the multiple follicular growth may not appear to pose a problem. However, at some point, which is totally unpredictable and which varies from individual to individual, endogenous estrogen can be produced such that the quantity of estrogen present can elevate blood levels well above 300 pg/ml. Indeed, estradiol concentration in plasma may exceed a few thousand in some instances. Therefore, while the use of an anti-estrogen seeks to reduce or modify or eliminate the side effects of estrogen, its use over time may have the reverse effect by inducing an excess concentration of estrogen. Not only may the use of the anti-estrogen exaggerate the estrogen side effects which it seeks to avoid, but the anti-estrogen may also even eliminate the primary benefit of the administration in the first instance. For example, a “run away” endogenous estrogen can induce ovulation in those situations where the administration of the anti-estrogen was designed to provide contraception. This feature of anti-estrogen therapy makes the establishment and maintenance of appropriate dosages of anti-estrogen difficult and in some cases impossible, especially when the therapeutic goal is simultaneous to limit excessive estrogenic impact in one tissue, while itself providing adequate estrogenic stimulation in another tissue.
It is therefore the object of the present invention to keep the hypothalamus and pituitary from becoming deranged and thereby prevent multiple follicular growth and the endogenous estrogen sustained, supraphysiological elevations which result from ovarian hyperstimulation. This and other objects of the invention will become apparent to those of ordinary skill in the art from the following detailed description.